Opioid agonist compounds

ABSTRACT

The present invention provides novel substituted opioid analgesic compounds of Formula I: ##STR1## which are opioid agonists, and which are useful as analgesic agents for the treatment of pain, pharmaceutical compositions comprising a therapeutically-effective amount of a compound of Formula I in combination with a pharmaceutically-acceptable carrier, and a method for eliminating or ameliorating pain in an animal comprising administering a therapeutically-effective amount of a compound of Formula I to the animal.

This application is a continuation-in-part application of co-pendingapplication Ser. No. 07/823,221, filed on Jan. 21, 1992, now U.S. Pat.No. 5,225,417.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention generally relates to compounds havingpharmacological activity which are useful as pharmacological agents and,more particularly, as analgesic agents for the treatment of pain, topharmaceutical compositions containing one or more of these compounds,and to methods of treatment employing these compounds. Moreparticularly, the present invention concerns novel opioid analgesiccompounds, pharmaceutical compositions containing one or more of thesecompounds in combination with a pharmaceutically-acceptable carrier, andmethods of treating pain employing these compounds.

Analgesic compounds are agents which alleviate pain without causing aloss of consciousness and, thus, which are useful for treating pain.

The major classes of analgesic compounds include narcotic analgesics, oropiates, compounds which alleviate pain and induce sleep, andanalgesic-antipyretic compounds, compounds which alleviate pain andreduce fever, such as salicylates.

Although the efficacy of opiates in relieving pain is well established,the associated addiction liability of opiates is a distinct disadvantageof these compounds.

While salicylate and salicylate-like agents (non-steroidalantiinflammatory agents or NSAIDS) are also efficacious in relievingpain, they often exhibit undesirable side effects, such asgastrointestinal irritation, as with aspirin, allergic response, as withaspirin, and/or liver toxicity with extended use, as with acetaminophen.

The compounds of the present invention are novel opioid agonistanalgesic compounds of comparable potency to morphine. The compoundshave the potential for reduced side effects such as abuse potential,addiction liability, tolerance, respiratory depression and/orconstipation, as compared to other agonists.

(2) Description of the Related Art

U.S. Pat. No. 4,816,586, issued on Mar. 28, 1989, discloses delta opioidreceptor antagonists of the formula: ##STR2## which are described asbeing useful for blocking delta-opioid receptors in mammalian tissue bycontacting the receptors with one of the delta-opioid antagonists of thenoted formulae. The antagonists are suggested for use as pharmacologicand biochemical probes of opioid receptor structure and function and foruse clinically, i.e., to counteract life-threatening shock.

The document described hereinabove discloses compounds which arestructurally different from the compounds of the present invention.Thus, the compounds of the present invention are structurally distinctfrom that which has been described in the art.

SUMMARY OF THE INVENTION

The present invention provides compounds having a structure of FormulaI: ##STR3## or a pharmaceutically-acceptable salt thereof, wherein: R¹represents hydrogen, C₁ -C₆ alkyl, C₃ -C₆ alkenyl, aryl, --CN, ##STR4##or --A--B, wherein n is an integer of from 1 to 5, and

wherein A represents alkylene and B represents aryl or arylalkylhydroxy;

R represents --H, --C₁ -C₅ alkyl, --C₃ -C₆ alkenyl or alkylaryl;

R² represents halogen, --NO₂, --NR⁷ R⁷, --SR⁷ or --OR⁴ ;

R³ represents hydrogen, C₁ -C₆ alkyl, aryl, aralkyl or ##STR5## R⁴represents hydrogen, C₁ -C₅ alkyl, ##STR6## aryl or alkylaryl; Xrepresents --NR⁶, O or S;

R⁵ represents hydrogen, C₁ -C₅ alkyl, C₁ -C₅ alkylaryl, C₃ -C₆ alkenyl,C₁ -C₅ alkoxy or arylalkoxy;

R⁶ represents hydrogen or C₁ -C₆ alkyl;

R⁷ represents hydrogen, C₁ -C₆ alkyl or ##STR7## alkyl; and Y representshydrogen, ##STR8## --CN, --CF₃, I or --SR⁶.

The present invention also provides pharmaceutical compositions whichare pharmaceutically acceptable and which comprise atherapeutically-effective amount of a compound of Formula I incombination with a pharmaceutically-acceptable carrier, and a method foreliminating or ameliorating pain in an animal comprising administering atherapeutically-effective amount of a compound of Formula I to theanimal.

DETAILED DESCRIPTION OF THE INVENTION

(1) Definitions

For purposes of clarity, the terms and phrases used throughout thisspecification and the appended claims are defined in the manner setforth directly below.

Some of the chemical structures which are presented in thisspecification and the appended claims have been drawn using theconvention which employs lines to represent alkyl radicals, which isknown by those of skill in the art.

The abbreviation "Ac" and the term "acetyl" as used herein mean thegroup ##STR9##

The abbreviations "AcOH" and "HOAc" as used herein mean ##STR10## andacetic acid.

The term "alkenyl" as used herein means a hydrocarbon radical havingfrom one to ten carbon atoms (C₁ -C₁₀), within which includes from oneto five carbon atoms (C₁ -C₅) and further within which includes from oneto three carbon atoms (C₁ -C₃), which can be a straight or branchedchain, and which contains from one to two --C═C-- groups.

The term "alkoxy" as used herein means an alkyl radical, as definedbelow, having an oxygen atom attached thereto, such as --O--C₁ -C₅ alkyl(C₁ -C₅ ) alkoxy). Representative alkoxy groups include methoxy, ethoxy,n-propoxy, tert-butoxy and the like.

The term "alkyl" as used herein means a saturated hydrocarbon radicalhaving from one to ten carbon atoms (C₁ -C₁₀) within which includes fromone to six carbon atoms (C.sub. -C₆), and further within which includesfrom one to three carbon atoms (C.sub. -C₃), which can be a straight orbranched chain. Representative of such radicals are methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl,2-ethylhexyl and the like.

The term "alkylaryl" as used herein means an alkyl radical, as definedabove, having an aryl group, as defined below, attached thereto.

The term "alkylhydroxy" as used herein means an alkyl radical, asdefined above, having a hydroxy group attached thereto, such as --C₁ -C₅--OH.

The term "alkylene" as used herein means a straight or branchedsaturated hydrocarbon chain spacer arm.

The term "analgesia" as used herein means the reduction, or absence, ofsensibility to pain, designating particularly the relief of pain withoutloss of consciousness.

The term "animal" as used herein includes mammals and non-mammals, andfurther includes humans and non-human animals.

The term "aryl" as used herein means 5- and 6-membered single-ringaromatic radicals which may include from zero to four heteroatoms in thering, and which further include from zero to two heteroatoms in thering, selected from oxygen, nitrogen and sulfur and which may beunsubstituted or be substituted with alkyl, halogen or alkoxy.Representative aryls include phenyl, thienyl, furanyl, pyridinyl,imidazolyl, thiazolyl, pyrimidinyl, pyrazinyl, pyridazinyl,(is)oxazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridinyl-N-oxide and thelike.

The term "aralkyl" as used herein means an aryl group, as defined above,having an alkyl group, as defined above, attached thereto, for examplephenylethyl and N-methylpyrrolyl.

The term "arylalkylhydroxy" as used herein means an aryl group, asdefined above, which has an alkylhydroxy group, as defined above,attached thereto.

The abbreviation "Boc" as used herein means t-butyloxycarbonyl.

The abbreviation "Bzl" and the term "benzyl" as used herein mean C₆ H₅CH₂ --.

The abbreviation "ca." as used herein means approximately.

The abbreviation "calcd" as used herein means calculated.

The term "carbonyl" as used herein means ##STR11##

The term "carboxyl" as used herein means ##STR12##

The abbreviation "cmpd" as used herein means compound.

The term "composition" as used herein means a product which results fromthe combining of more than one ingredient.

The abbreviation "DMF" as used herein means dimethylformamide.

The phrase "EC₅₀ dose" as used herein means that dose of a compound ordrug which is necessary to elicit a 50% maximal biological response and,thus, which is necessary to elicit a 50% reduction in the contractionsof guinea pig ileum segments in a prostaglandin antagonism assay.

The phrase "ED₅₀ dose" as used herein means that dose of a compound ordrug which produced a defined biological effect, such as producinganalgesia, in 50% of the animals to which the compound or drug wasadministered.

The abbreviation "equiv" as used herein means equivalent.

The abbreviation "Et" as used herein means ethyl (--CH₂ CH₃) .

The abbreviation "EtOH" as used herein means ethanol (CH₃ CH₂ OH).

The term "flash chromatography" as used herein is described in J. Org.Chem. 1978, 43,2923.

The abbreviation "¹ H NMR" as used herein means Proton Nuclear MagneticResonance.

The term "halo" or "halogen" as used herein means chlorine (Cl), bromine(Br), fluorine (F) and/or iodine (I).

The term "heteroatom" as used herein means an atom of any element otherthan carbon or hydrogen.

The abbreviation "i.g." and the term "intragastrically" as used hereinmean that a compound or drug was administered into the stomach.

The abbreviation "Me" as used herein means methyl (--CH₃).

The abbreviation "MeI" as used herein means methyl iodide.

The abbreviation "MeOH" as used herein means methanol (CH₃ OH).

The abbreviation "NC" as used herein means not calculated.

The phrase "N-protecting group" or "N-protected" as used herein meansthose groups intended to protect the N-terminus of an amino acid orpeptide, to protect an amino group against undesirable reactions duringsynthetic procedures and includes, but is not limited to, sulfonyl,acyl, acetyl, pivaloyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl(Cbz), benzoyl and an L- or D-aminoacyl residue, which may itself beN-protected similarly.

The phrases "parenteral administration" and "administered parenterally"as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The abbreviation "Ph" and the term "phenyl" as used herein mean thegroup C₆ H₅ --, derived from benzene.

The phrase "pharmaceutically acceptable" is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically-acceptable carrier" as used herein means apharmaceutically-acceptable material, composition or vehicle, as defineddirectly above, such as a liquid or solid filler, diluent, excipient,solvent or encapsulating material, involved in carrying or transportinga chemical compound or pharmaceutical agent from one organ, or portionof the body, to another organ, or portion of the body. Some examples ofmaterials which can serve as pharmaceutically-acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) excipients, such as cocoa butter and suppository waxes; (9)oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; (10) glycols, such as propyleneglycol; (11) polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; (12) esters, such as ethyl oleate and ethyllaurate; (13) agar; (14) buffering agents, such as magnesium hydroxideand aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17)isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

The phrase "pharmaceutically-acceptable salts" as used herein refers tonon-toxic salts of the compounds of the present invention which aregenerally prepared by reacting the free base with a suitable organic orinorganic acid, or which are prepared by reacting the free acid with asuitable base. Representative salts include the hydrochloride,hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, palmitate,stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate,maleate, fumarate, succinate, tartrate, napsylate, clavulanate and thelike salts and alkali metal salts such as sodium and potassium andalkaline earth salts, such as calcium and magnesium.

The phrase "protecting group" as used herein means substituents whichprotect the reactive functional group from undesirable chemicalreactions. Examples of such protecting groups include esters ofcarboxylic acids, ethers of alcohols and acetals and ketals of aldehydesand ketones.

The abbreviation "pyr" as used herein means pyridine.

The abbreviation "s.c." as used herein means that a compound or drug wasadministered subcutaneously.

The phrase "therapeutically-effective amount" as used herein means anamount of a compound, material, or composition which is an effectivedose for eliminating or ameliorating pain in an animal, or for producingsome other desired therapeutic effect, at a reasonable benefit/riskratio applicable to any medical treatment.

The abbreviation "THF" as used herein means tetrahydrofuran.

The phrases "title compound," "title product," "title peptide" and"title material" as used herein mean that compound, product, peptide ormaterial whose chemical name is given, and whose structure is shown, inthe particular example, or subpart thereof, referred to. If noparticular example, or subpart thereof, is referred to, it means thatcompound, product, peptide or material whose chemical name is given, andwhose structure is shown, in the particular example, or subpart thereof,in which it appears.

(2) Description of Invention

In one aspect, the present invention provides compounds comprising astructure of Formula I, as described above, andpharmaceutically-acceptable salts, esters and amides thereof.

The compounds of the present invention comprise a class of substitutedmorphinan compounds which compounds have been shown to exhibit activityas opioid agonists.

Specific compounds within the scope of the invention include, but arenot limited to, the compounds discussed in the examples presented below,as well as their pharmaceutically-acceptable salts, esters, and amides.

Contemplated equivalents of the compounds described in Formula I includecompounds which otherwise correspond thereto, and which have the samegeneral properties thereof, wherein one or more simple variations ofsubstituents are made which do not adversely affect the efficacy of thecompound.

Certain compounds of the present invention may contain a basicfunctional group, such as amino or alkylamino, and are, thus, capable offorming pharmaceutically-acceptable salts withpharmaceutically-acceptable acids. The term "pharmaceutically-acceptablesalts" in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ during the final isolation andpurification of the compounds of the invention, or by separatelyreacting a purified compound of the invention in its free base form witha suitable organic or inorganic acid, and isolating the salt thusformed. Representative salts include the hydrobromide, hydrochloride,sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate,palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate,citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate,glucoheptonate, lactobionate, and laurylsulphonate salts and the like.(See, for example, S. M. Berge et al., "Pharmaceutical Salts," J PharmSci., 66:1-19 (1977).)

In other cases, the compounds of the invention may contain one or moreacidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term "pharmaceutically-acceptable salts" in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ during the final isolation and purification of thecompounds, or by separately reacting the purified compound in its freeacid form with a suitable base, such as the hydroxide, carbonate orbicarbonate of a pharmaceutically-acceptable metal cation, with ammonia,or with a pharmaceutically-acceptable organic primary, secondary ortertiary amine. Representative alkali or alkaline earth salts includethe lithium, sodium, potassium, calcium, magnesium, and aluminum saltsand the like. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine, ethylenediamine,ethanolamine, diethanolamine, piperazine and the like. (See, forexample, S. M Berge et al., "Pharmaceutical Salts," supra.)

In another aspect, the present invention providespharmaceutically-acceptable compositions which comprise atherapeutically-effective amount of one or more of the compounds ofFormula I, as described hereinabove, formulated together with one ormore pharmaceutically-acceptable carriers. The pharmaceuticalcompositions of the invention may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal or vaginal administration.

In yet a further aspect, the present invention provides a method foreliminating or ameliorating pain in an animal, and methods for treatingcentral nervous disorders, including convulsions and ischemia, andasthma, enuresis, arrhythmia, diarrhea, dysmenorrhea and osteoporosis inan animal, comprising administering a therapeutically-effective amountof a compound of Formula I, as described hereinabove, to the animal.

The most preferred embodiment of the present invention is the compounddescribed in Example 9 below.

(3) Utility

Compounds of the present invention exhibit activity as opioid agonistanalgesics.

Compounds within the present invention, and the pharmaceuticalcompositions comprising one or more of these compounds, are useful asanalgesic agents for the elimination or amelioration of pain in animals.

4) Methods of Preparation

In general, the compounds of the present invention may be prepared bythe methods illustrated in the following general reaction schemes, or bymodifications thereof, using readily-available starting materials,reagents and conventional synthesis procedures. Unless otherwisespecified, the various substituents of the compounds and materialspresent in the general reaction schemes are defined in the same manneras they are defined above in Formula I.

If a particular enantiomer of a compound of the present invention isdesired, it may be prepared by chiral synthesis, by derivation with achiral auxiliary, where the resulting diastereomeric mixture isseparated and the auxiliary group cleaved to provide the pure desiredenantiomers or by synthetic modification of a chiral enantiomericallyenriched material. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

The compounds of this invention may be prepared by the methodsillustrated in one or more of the three general reaction schemespresented hereinbelow.

General Reaction Scheme No. 1 depicts the cyclization reaction to formthe indole or benzofuran ring system. The known morphinoid ketones (R¹=hydrogen, C₁ -C₆ alkyl, C₃ -C₆ alkenyl, aryl, --CN, ##STR13## or--A--B, wherein n is an integer of from 1 to 5, wherein R is --OH,--O--C₁ -C₅ alkyl, --O--C₃ -C₆ alkenyl or alkylaryl and wherein A isalkylene and B is aryl or arylalkylhydroxy; R² =halogen, --NO₂, --NR⁷R⁷, SR⁷ or OR⁴, wherein R⁷ is hydrogen, C₁ -C₆ alkyl or ##STR14## alkyland wherein R⁴ is hydrogen, C₁ -C₅ alkyl, ##STR15## aryl or alkylaryl;and R³ =hydrogen, C₁ -C₆ alkyl, aryl, aralkyl or ##STR16## wherein R⁵ ishydrogen, C₁ -C₅ alkyl, C₁ -C₅ alkylaryl, C₃ -C₆ alkenyl, C₁ -C₅ alkoxyor arylalkoxy) were treated with a substituted or unsubstituted phenylhydrazine (X=NH; and Y=H) or a substituted or unsubstituted O-phenylhydroxylamine (X=O, S or NR⁶, wherein R⁶ is C₁ -C₆ alkyl; and Y=##STR17## --CN, --CF₃, I or SR⁶, wherein R is as defined above, andwherein R⁶ is hydrogen or C₁ -C₆ alkyl) using an appropriate solvent andacid catalyst to give the desired products.

General Reaction Scheme No. 2 shows the reaction sequence used to effectthe removal of the methyl group on the nitrogen and subsequentreplacement with the various R¹ groups discussed above for GeneralReaction Scheme No. 1. In General Reaction Scheme No 2, R² is --OH, R³and Y are each hydrogen and X is oxygen. Thus, the C-3 and C-14 hydroxylgroups are protected by treatment with acetic anhydride and pyridine togive the diacetoxy compound. Treatment of this compound with cyanogenbromide in chloroform yields the N-cyano compound No. 1. Treatment ofcompound No. 1 with aqueous sodium hydroxide in ethanol gives compoundNo. 2. Three methods were used to add various R¹ groups to give novelcompounds. Method a involves alkylation in dimethylformamide using ahalo-substituted R¹. Compound Nos. 3, 4, 8, and 16 were prepared in thismanner. Method b involves the reaction of compound No. 2 with acarboxylic acid chloride to form a carboxylic acid amide. Reduction withlithium tetrahydroaluminate yields novel R¹ =alkyl or aryl-substitutedmorphinoids. Method c involves reductive amination with compound No. 2using sodium cyanoborohydide and an appropriate aldyedyde. CompoundsNos. 7, 13, 14, and 15 were prepared via method c. All othercontemplated R¹ substitutions can be prepared via these three methods.

General Reaction Scheme No. 3 depicts the general method to installvarious R⁴ substitutions into the compounds of the invention. In GeneralReaction Scheme No. 3, R¹, X and Y are each as defined above for GeneralReaction Scheme No 1, R² is --OR⁴ wherein R4 is as defined above forGeneral Reaction Scheme No. 1, and R³ is hydrogen. Thus, the C-3hydroxyl was selectively methylated using potassium hydride andiodomethane to give the C-3 O-methyl compound. Further treatment withpotassium hydride and an appropriate organohalide installs the R⁴ groupon the C-14 hydroxyl. Demethylation via standard conditions, such asboron tribromide or sodium ethanethiolate in methylene chloride, yieldsnovel compounds with a C-14 --OR⁴ substitution.

Where specific compounds are referred to hereinabove, for example,compound No. 1, the compounds referred to are those compounds which areshown and described in the examples presented hereinbelow. ##STR18##

While the various aspects of the present invention are described hereinwith some particularity, those of skill in the art will recognizenumerous modifications and variations which remain within the spirit ofthe invention. These modifications and variations are within the scopeof the invention as described and claimed herein.

(5) Examples

The following examples describe and illustrate the methods for thepreparation of the compounds of the present invention, as well as otheraspects of the present invention, and the results achieved thereby, infurther detail. Both an explanation of, and the actual procedures for,the various aspects of the present invention are described whereappropriate. These examples are intended to be merely illustrative ofthe present invention, and not limiting thereof in either scope orspirit. Those of skill in the art will readily understand that knownvariations of the conditions and processes of the preparative proceduresdescribed in these examples can be used to prepare the compounds of thepresent invention, and the pharmaceutical compositions comprising suchcompounds.

In the examples, all parts are by weight unless otherwise indicated.

All starting materials and equipment employed in the examples arecommercially available. Sources for these materials incolude SigmaChemical Co. (St. Louis, Mo.), Aldrich Chemical Co. (Milwaukee, Wis.,Lancaster Synthesis (Windham, N.H.), Fisher Scientific (Pittsburgh,Pa.), Boehringer Mannheim Biochemicals (Indianapolis, Ind.), FlukaChemical Corp. (Ronkonkoma, N.Y.), Mallinckrodt Chemical Co. (St. Louis,Mo.), and Chemical Dynamics Corp. (South Plainfield, N.J.). Most of thestarting materials were obtained from Aldrich Chemical Co. (Milwaukee,Wis.) or Mallinckrodt Chemical Co. (St. Louis, Mo.).

All patents and publications referred to in the examples, and throughoutthe specification, are hereby incorporated herein by reference, withoutadmission that such is prior art.

    __________________________________________________________________________                                                      Optical                     Cmpd.                        Molecular Microanalysis                                                                            Rotation                    No. Structure                Formula      Calcd                                                                             Found                                                                             [α].sub.D             __________________________________________________________________________     1                                                                                 ##STR19##               C.sub.27 H.sub.22 N.sub.2 O.sub.6                                                       C H N                                                                            68.93  4.71  5.95                                                                 68.81  4.81  5.44                                                                 -387.7°               2                                                                                 ##STR20##               C.sub.22 H.sub.19 N0.sub.4 + 0.3 H.sub.2                                                C H N                                                                             72.04  5.39  3.82                                                                71.95  5.55  3.79                                                                 NC                           3                                                                                 ##STR21##               C.sub.27 H.sub.28 NO.sub.4 Cl + O.4 H.sub.2                                   O         C H N Cl                                                                         68.53  6.14  2.96  7.49                                                           68.58  5.97  2.91  7.45                                                           -370.8°               4                                                                                 ##STR22##               C.sub.26 H.sub.25 NO.sub.6 + 0.8 HCl + 0.2                                    H.sub. 2 O                                                                              C H N Cl                                                                         65.02  5.50  2.92  5.91                                                           65.03  5.39  2.90  5.62                                                           -390.6°               5                                                                                 ##STR23##               C.sub.24 H.sub.23 N.sub.2 O.sub.5 Cl + 1.0                                    H.sub.2 O C H N Cl                                                                         60.95  5.33  5.92  7.50                                                           61.18  5.09  5.99  8.08                                                           -251.6°               6                                                                                 ##STR24##               C.sub.26 H.sub.28 N.sub.2 O.sub.5 Cl + 0.5                                    H.sub.2 O C H N                                                                            63.47  5.74  5.69                                                                 63.46  5.79  5.61                                                                 -330.8°               7                                                                                 ##STR25##               C.sub.30 H.sub.28 NO.sub.4 Cl + 0.2 HCl +                                     0.2 EtOH  C H N Cl                                                                         70.42  5.72  2.72  8.21                                                           70.59  5.63  2.70  8.00                                                           -339.4°               8                                                                                 ##STR26##               C.sub.24 H.sub.21 NO.sub.6 + 0.9 HCl + 1.0                                    H.sub.2 0 C H N Cl                                                                         61.30  5.12  2.98  6.79                                                           61.11  4.93  3.29  6.40                                                           -372.5°               9                                                                                 ##STR27##               C.sub.24 H.sub.24 NO.sub.4 Cl + 1.3 H.sub.2                                   O         C H N Cl                                                                         64.15  5.97  3.12  7.89                                                           63.97  5.57  3.06  7.53                                                           -376.6°              10                                                                                 ##STR28##               C.sub.30 H.sub.28 NO.sub.4 Cl + 1.1 H.sub.2                                   O         C H N Cl                                                                         69.05  5.83  2.68  6.79                                                           68.84  5.53  2.64  6.94                                                           -346.0°              11                                                                                 ##STR29##               C.sub.26 H.sub.24 N.sub.2 O.sub.5 + 0.88 HCl                                  + 1.75 H.sub.2 O                                                                        C H N Cl                                                                         61.48  5.63  5.52  6.11                                                           61.56  5.23  5.47  5.75                                                           -213.2°              12                                                                                 ##STR30##               C.sub.23 H.sub.22 N.sub.2 O.sub.3 ClI + 0.2                                   H.sub.2 O C H N Cl                                                                         51.12  4.18  5.18  6.56                                                           50.73  4.20  5.12  6.73                                                           NC                          13                                                                                 ##STR31##               C.sub.28 H.sub.26 NO.sub.6 Cl + 1.5 H.sub.2                                   O         C H N Cl                                                                         62.86  5.46  2.62  6.63                                                           62.93  5.09  2.64  6.85                                                           NC                          14                                                                                 ##STR32##               C.sub.27 H.sub.27 NO.sub.6 Cl + 1.5 H.sub.2                                   O         C H N Cl                                                                         63.09  5.43  2.72  7.59                                                           63.00  4.74  2.69  7.73                                                           NC                          15                                                                                 ##STR33##               C.sub.26 H.sub.24 N.sub.3 O.sub.4 Cl + 1.0                                    H.sub.2 O + 0.8 HCl                                                                     C H N Cl                                                                         59.47   5.14  8.00 12.15                                                          59.29  4.93  7.93 12.18                                                           NC                          16                                                                                 ##STR34##               C.sub.29 H.sub.25 NO.sub.4 + 0.5 C.sub.6                                      H.sub.14 O                                                                              C H N                                                                            76.47  6.42  2.79                                                                 76.15  6.22  2.83                                                                 -481.1°              __________________________________________________________________________

EXAMPLE I1,8aβ-Bis(acetloxy)-5,6,8,8a,9,14bβ-hexahydro-4,8(R,α)-methano-4bS*-7H-bisbenzofuro-[3,2-e:2',3'-g]isoquinoline-7-carbonitrile(Compound 1)

6,7,8,14bβ-tetrahydro-7-methyl-4,8 (R,α)-methano4bS*-5H-bisbenzofuro[3,2e:2',3'-g]isoquinoline-1, 8aβ(9H)-diol, monohydrochloride (2.50 g, 6.66mmol) was slurried in a mixture of acetic anhydride (60 mL) and pyridine(30 mL) and stirred for 21 hours at room temperature whereupon a newprecipitate formed. The volatiles were removed by rotary evaporation andthe residue was taken up into water (100 mL) and extracted withchloroform (2×100 mL). The combined organic extracts were dried (Na₂SO₄), filtered and evaporated in vacuo to give a residue which wasrecrystallized from ethyl acetate/chloroform to give3,14-diacetoxy-6,7,2',3'-benzofuran-6,7-dehydro-4,5α-epoxy-3,14-dihydroxy-17-methylmorphinanas a white solid. ¹ H NMR (CDCl₃) δ7.49 (d, J=8 Hz, 1H), 7.38 (d, J=8Hz, 1H), 7.29 (t, J =8 Hz, 1H), 7.18 (t, J=8 Hz, 1H), 6.81 (d, J=8 Hz,1H), 6.68 (d, J=8 Hz, 1H), 5.65 (s, 1H), 4.41 (d, J=7 Hz, 1H), 3.71 (d,J=18 Hz, 1H), 3.30 (d, J=18 Hz, 1H), 2.71 (dd, J=7, 18 Hz, 1H),2.58-2.45 (comp m, 3H), 2.36 (s, 3H), 2.27 (m, 1H), 2.26 (s, 3H), 1.97(s, 3H), 1.80 (m, 1H).

The above compound (2.14 g, 4.66 mmol) was dissolved in chloroform (50mL) and treated with cyanogen bromide (1.97 g, 18.6 mmol). The mixturewas heated to reflux for 48 hours before cooling to room temperature.The solution was diluted with chloroform and washed with 1N aqueoushydrochloric acid (50 mL) and water (50 mL), then dried (Na₂ SO₄),filtered and evaporated in vacuo to give a crude residue which wasrecrystallized from ethyl acetate/hexane to provide the title compoundas a white solid. ¹ H NMR (CDCl₃) δ7.51 (d, J=8 Hz, 1H), 7.38 (d, J=8Hz, 1H), 7.33 (t, J=8 Hz, 1H), 7.22 (t, J=8 Hz, 1H), 6.90 (d, J=8 Hz,1H), 6.76 (d, J=8 Hz, 1H), 5.66 (s, 1H), 5.11 (m, 1H), 3.95 (d, J=18 Hz,1H), 3.42-3.20 (comp m, 4H), 2.67 (dt, J=7, 14 Hz, 1H), 2.51 (m, 1H),2.27 (s, 3H), 2.09 (s, 3 H), 1.88 (m, 1H).

EXAMPLE II6,7,8,14bβ-Tetrahydro-4,8(R,α)-methano-4bS*-5H-bisbenzofuro[3,2-e:2',3'-g]isoquininoline-1,8aβ(9H)-diol(Compound 2 )

Compound 1 (4.66 mmol) was slurried in a 1:1 mixture of 25% aqueoussodium hydroxide/ethanol and stirred at room temperature untilhomogeneous. The mixture was then heated at reflux for 70 hours beforecooling to room temperature. The mixture was diluted with water (100 mL)and washed with ether (2×100 mL). The aqueous phase was made acidic with12N hydrochloric acid and then filtered to remove nonbasic solidmaterial. The filtrate was made basic with concentrated aqueous ammoniumhydroxide and the resulting solid was filtered, washed with water anddried in vacuo to give the title compound as a tan solid. ¹ H NMR (DMSOd₆) δ9.18 (br s, 1H), 7.58 (d, J=8 Hz, 1H), 7.48 (d, J=8 Hz, 1H), 7.32(t, J=8 Hz, 1H), 7.22 (t, J=8 Hz, 1H), 6.56 (comp m, 2H), 5.53 (s, 1H),4.8 (brs, 1H), 3.40-2.10 (comp m, 8H), 1.52 (m, 1H).

EXAMPLE III6,7,8,14bβ-tetrahydro-7-(3-methyl-2-butenyl)-4,8-(R,α)-methano-4bS*-5H-bisbenzofuro[3,2-e:2',3'-g]-isoquinoline-1,aβ(9H)-diol,monohydrochloride (Compound 3)

To a slurry of compound 2 (235 mg, 0,650 mmol) in dimethylformamide (5mL) was added potassium carbonate (99 mg, 0.71 mmol) and4-bromo-2-methyl-2-butene (107 mg, 0.72 mmol), and the resulting mixturewas heated to 90°-100° C. for 3.5 hours. The mixture was cooled to roomtemperature and diluted with water (25 mL) before extracting with ethylacetate (3×25 mL). The combined organic extracts were dried (Na₂ SO₄),then filtered and evaporated in vacuo to give a residue which waspurified by silica gel chromatography (eluting with 5% methanol inmethylene chloride) to give the free base of compound 3. The free basewas taken up in ethanol (ca. 5 mL) and treated with 200 μL of a 7Mhydrogen chloride solution in dioxane. The hydrochloride salt wasprecipitated by the addition of excess ether to give the title compoundas a white solid. For the free base of the title compound: ¹ H NMR(CDCl₃) δ7.44 (d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.27 (t, J=8 Hz,1H), 7.16 (t, J=8 Hz, 1H), 6.65 (d, J=8 Hz, 1H), 6.58 (d, J=8 Hz, 1H),5.63 (s, 1H), 5.22 (m, 1H), 4.97 (br s, 2H), 3.23-3.13 (comp m, 2H),2.84-2.72 (comp m, 3 H), 2.61 (comp m, 2H), 2.32 (m, 2H), 1.83-1.62(comp m, 2H), 1.78 (s, 3H), 1.69 (s, 3H) .

EXAMPLE IV Ethyl5,6,8,8a,9,14bβ-hexahydro-1,8aβ-dihydroxy-4,8(R,α)-methano-4bS*-7H-bisbenzofuro-3,2-e:2',3'-g]isoquinoline-7-acetate,hydrochloride (Compound 4)

The title compound was prepared as described in Example III except thatethyl bromoacetate was used in place of the 4-bromo-2-methyl-2-butene.For the free base of the title compound: ¹ H NMR (CDCl₃) δ7.43 (d, J =8Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.26 (t, J=8 Hz, 1H), 7.16 (t, J=8 Hz,1H), 6.67 (d, J=8 Hz, 1H), 6.58 (d, J=8 Hz, 1H), 5.66 (s, 1H), 4.98 (s,1H), 4.76 (s, 1H), 4.22 (q, J=7 Hz, 2H), 3.38 (ab q, J=17 Hz, 2H) , 3.14(dd, J=6, 12 Hz, 2H) , 2.95-2.80 (comp m, 2H), 2.68-2.45 (comp m, 2H),2.82 (m, 1H), 1.30 (t, J=7 Hz, 3H).

EXAMPLE V

5,6,7,8,8a,9,14,14bβ-Octahydro-1,8aβ-dihydroxy-7-methyl-4,8(R,.alpha.)-methano-4bS*-benzofuro[2,3-a]pyrido-4,3-b]carbazole-11-carboxylicacid, monohydrochloride

(Compound 5 )

A slurry of oxymorphone hydrochloride (3.00 g, 8.88 mmol) and4-hydrazinobenzoic acid (1.45 g, 9.50 mmol) in glacial acetic acid (50mL) was treated with 6N hydrogen chloride in dioxane (1.9 mmol, 11.4mmol) and then heated to reflux for 5 minutes. The mixture was cooled toroom temperature and the resulting brown solid was collected byfiltration and washed with ether to provide the title compound as a tansolid after drying under vacuum. ¹ H NMR (CD₃ OD) δ8.17 (s, 1H), 7.81(d, J=8 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 6.67 (comp m, 2H), 5.70 (s, 1H),3.81 (d, J=6 Hz, 1H), 3.51 (d, J=16 Hz, 1H), 3.36-2.68 (comp m, 5H),2.98 (s, 3H), 1.93 (m, 1H).

EXAMPLE VI Ethyl5,6,7,8,8a,9,14,14bβ-Octahydrol,8αP-dihydroxy-7-methyl-4,8(R,.alpha.)methano-4bS*-benzofuro-[2,3-a]pyrido[4,3-b]carbazole-11-carboxylate,monohydrochloride (Compound 6)

Compound 5 (750 mg, 1.59 mmol) was taken up in ethanol saturated withhydrogen chloride (10 mL) and stirred at room temperature for 48 hours.The volatiles were removed by rotary evaporation and the residue wastaken up in water (25 mL). The mixture was made basic with concentratedaqueous ammonium hydroxide and then extracted with ethyl acetate (3×25mL). The combined organic extracts were dried (Na₂ SO₄), filtered andevaporated in vacuo to give a residue which was purified by silica gelchromatography (eluting with 7% methanol in methylene chloride) to givethe free base of the title compound. The free base was taken up intoethanol, and ethanol saturated with hydrogen chloride was added. Theaddition of excess ether precipitated a solid which was collected anddried to provide the title compound as a white solid. For the free baseof the title compound: ¹ H NMR (CDCl₃) δ8.90 (br s, 1H), 7.98 (s, 1H),7.56 (d, J=8 Hz, 1H), 6.78 (d, J=8 Hz, 1H), 6.55 (d, J=8 Hz, 1H), 6.46(d, J=8 Hz, 1H), 5.55 (s, 1H), 5.5 (br s, 1H), 4.34 (q, J=7 Hz, 2H),3.16 (d, J=18 Hz, 1H), 2.97 (d, J=7 Hz, 1H), 2.83-2.70 (comp m, 2H),2.51 (d, J=16 Hz, 1H), 2.36 (s, 3H), 2.40-2.20 (comp m, 3H), 1.60 (m,1H), 1.37 (t, J=7 Hz, 3H).

EXAMPLE VII 6,7,8,14bβ-tetrahydro-7-(2-phenylethyl)-4,8(R,α)-methano-4bS*-5H-bisbenzofuro[3,2-e:2',3'-g]-isoquinoline-1,8aβ(9H)-diol,hydrochloride (Compound 7)

To a slurry of Compound 2 (180 mg, 0.498 mmol) in methanol (5 mL) wasadded glacial acetic acid (45 mg, 0.75 mmol) and phenylacetaldehyde (72mg, 0.56 mmol). The mixture was stirred for 10 minutes at roomtemperature before the addition of sodium cyanoborohydride (63 mg, 1.0mmol). After stirring for 30 hours, 6N HCl was added (5 mL) and themixture was stirred an additional 30 minutes before the removal of thesolvent by rotary evaporation. The residue was taken up into water (25mL) and extracted with diethyl ether (2×25 mL). The aqueous phase wasmade basic with concentrated ammonium hydroxide, and the resultingcloudy mixture was extracted with ethyl acetate (3×25 mL). The combinedethyl acetate extracts were dried (Na₂ SO₄), filtered and evaporated invacuo to give a residue which was purified by silica gel chromatography(eluting with 5% methanol in methylene chloride) to give the free baseof the title compound. The free base was taken up into methanol, and asolution of 7M HCl in dioxane was added (0.2 mL). The addition of excessether precipitated a solid which was collected and dried to provide thetitle compound as a white solid. ¹ H NMR (DMSO d-6) δ9.18 (s, 1H), 9.07(br s, 1H), 7.43 (d, J=7 Hz, 1H), 7.31 (d, J=7 Hz, 1H), 7.22-7.07 (compm, 7H), 6.48 (m, 2H), 5.59 (s, 1H), 3.89 (br d, J=8 Hz, 1H), 3.41-2.37(comp m, 11H), 1.67 (m, 1H).

EXAMPLE VIII5,6,8,8a,9,14bβ-Hexahydro-1,8aβ-dihydroxy-4,8-(R,α)-methano-4bS*-7H-bisbenzofuro[3,2-e:2',3'-g]-isoquinoline-7-aceticacid, hydrochloride (Compound 8)

Compound 4 (124 mg, 0,277 mmol) was taken up into 4N HCl (10 mL) andheated to reflux for 3 hours. The mixture was cooled to room temperatureand the solvent was removed by rotary evaporation. The residue wasrecrystallized from methanol/isopropyl ether to give the title compoundas a tan solid. ¹ H NMR (DMSO d-6) δ9.02 (br s, 1H), 7.33 (d, J=7 Hz,1H), 7.22 (d, J=7 Hz, 1H), 7.08 (t, J=7 Hz, 1H), 6.97 (t, J=7 Hz, 1H)6.34 (m, 2H), 5.43 (s, 1H), 3.81-2.23 (comp m, 10H), 1.51 (m, 1H).

EXAMPLE IX6,7,8,8a,9,14bβ-hexahydro-8aβ-methoxy-7-methyl-4,8(R,α)-methano-4bS*-5H-bisbenzofuro-[3,2-e:2',3,-g]isoquinolin-1-ol,monohydrochloride (Compound 9)

Potassium hydride (KH) as a 35% dispersion in oil (275 mg dispersion,2.40 mmol) was washed via slurrying in pentane (10 mL), followed by theremoval of the supernatant oil/pentane from the solid KH. The KH wasslurried in THF (15 mL) and cooled to 0° C. and6,7,8,14bβ-tetrahydro-7-methyl-4,8(R,α)-methano-4bS*-5H-bisbenzofuro[3,2-e:2',3'-g]isoquinoline-1,8aβ(9H)-diol(300 mg, 0,799 mmol) was added. The mixture was warmed to roomtemperature and stirred for 25 minutes before an addition of iodomethane(580 mg, 4.00 mmol). The resulting cloudy mixture was stirred for 30minutes before pouring it into 1N HCl (25 mL). The mixture was madebasic with concentrated ammonium hydroxide and then extracted with ethylacetate (3×25 mL). The combined extracts were dried (Na₂ SO₄), filteredand evaporated in vacuo to give a residue of 3,14-dimethoxy morphinan.

The residue from above was dissolved in methylene chloride (30 mL) andcooled to -78° C. wherein it was treated with boron tribromide (2.04 g,8.1 mmol). The resulting red solution was allowed to warm to -30° C. andstirred for 45 minutes. The mixture was recooled to -78° C. and treatedwith methanol (5 mL) and then allowed to warm to room temperature. Thesolution was poured into 1N HCl (25 mL) and then made basic withconcentrated ammonium hydroxide. The mixture was then extracted withmethylene chloride (2×25 mL). The combined organic extracts were dried(Na₂ SO₄), filtered, and evaporated in vacuo to give a residue (320 mg)which was purified by silica gel chromatography (eluting with 5%methanol in methylene chloride) to give the free base of the titlecompound. The free base was taken up into methanol and a solution of 7MHCl in dioxane was added (0.15 mL). The addition of excess etherprecipitated a solid which was collected and dried to provide the titlecompound as a white solid. For the free base of the title compound: ¹ HNMR (CDCl₃) δ7.47 (d, J=8 Hz, 1H), 7.38 (d, J-7 Hz, 1H), 7.27 (t, J=7Hz, 1H), 7.19 (t, J=7 Hz, 1H), 6.66 (d, J=7 Hz, 1H), 6.57 (d, J=7 Hz,1H), 5.63 (s, 1H), 3.39-3.29 (comp m, 2H), 3.25 (s, 3H), 3.02 (d, J= 16Hz, 1H), 2.60 comp m, 3H), 2.43 (s, 3H), 2.33 (d, J =16 Hz, 1H), 2.28(m, 1H), 1.68 (dd, J=4, 11 Hz, 1H).

EXAMPLE X6,7,8,8a,9,14bβ-hexahydro-7-methyl-8aβ-(phenylmethoxy)-4,8(R,.alpha.)-methano-4bS*-5H-bisbenzofuro[3,2-e:2',3'-g]isoquinolin-1-ol,monohydrochloride (Compound 10)

Sodium hydride, as a 60% dispersion in oil (112 mg dispersion, 2.80mmol) was washed with pentane (5 mL) to remove the oil and thensuspended in dimethylformamide (DMF, 20 mL) and cooled in an ice bath.6,7,8,14bβ-tetrahydro-7-methyl-4,8(R,α)-methano-4bS*-5H-bisbenzofuro[3,2-e:2',3'-g;9isoquinoline-1,8aβ(9H)-diol (1.00 g, 2.66 mmol) was added in one portionand the mixture was stirred for 20 minutes before an addition ofiodomethane (772 mg, 5.33 mmol). The mixture was stirred for 15 minutesat 0° C. and 45 minutes at room temperature and then poured into 0.5Naqueous HCl (50 mL). The mixture was extracted with diethyl ether (50mL) and the aqueous phase was made basic with concentrated aqueousammonium hydroxide. The cloudy solution was extracted with ethyl acetate(3×50 mL) and the combined organic extracts were washed with water (2×50mL), then dried (Na₂ SO₄), filtered and evaporated in vacuo to give thecrude product. The product was purified by silica gel chromatography,eluting with 5% methanol in methylene chloride to give the 3-methoxyderivative.

Potassium hydride (KH) as a 35% dispersion in oil (148 mg dispersion,1.29 mmol) was washed via slurrying in pentane (5 mL), followed by theremoval of the supernatant oil/pentane from the solid KH. The 3-methoxyderivative (335 mg, 0,800 mmol) was added as a solution in 5 mL DMF tothe KH and stirred for 20 minutes before an addition of benzyl bromide(294 mg, 1.72 mmol). After stirring for 44 hours, the mixture was pouredinto 1N aqueous HCl (25 mL) and extracted with diethyl ether (25 mL).The aqueous phase was made basic with concentrated aqueous ammoniumhydroxide and then extracted with ethyl acetate (2×25 mL). The combinedethyl acetate extracts were dried (Na₂ SO₄), filtered, then evaporatedin vacuo to give a residue which was purified by silica gelchromatography, eluting with 2% methanol in methylene chloride to givethe 3-methoxy-14-benzyloxy intermediate.

Sodium hydride, as a 60% dispersion in oil (163 mg dispersion, 4.06mmol) was washed with hexane (5 mL) to remove the oil and then suspendedin dimethylformamide (DMF, 2 mL). Ethanethiol (202 mg, 3.25 mmol) wasadded and the mixture was stirred for 20 minutes whereupon a yellowprecipitate formed. The 3-methoxy-14-benzyloxy compound (78 mg, 0.16mmol) was added as a solution in 4 mL DMF and the mixture was heated to125°-135° C. for 4 hours. The mixture was cooled to room temperature andpoured into 1N aqueous HCl (25 mL). The mixture was extracted withdiethyl ether (2×25 mL) to remove neutral organics and then made basicwith concentrated aqueous ammonium hydroxide. The mixture was extractedwith ethyl acetate (2×25 mL), and the combined ethyl acetate extractswere dried (Na₂ SO₄), filtered, then evaporated in vacuo. The resultingresidue was purified by silica gel chromatography, eluting with 5%methanol in methylene chloride to give the free base of the titlecompound. The free base was taken up into methanol and a solution of 7MHCl in dioxane was added (0.15 mL). The addition of excess etherprecipitated a solid which was collected and dried to provide the titlecompound as a white solid. For the free base of the title compound: ¹ HNMR (CDCl₃) δ7.42 (d, J=7 Hz, 1H), 7.28 (d, J=7 Hz, 1H), 7.23 (t, J=7Hz, 1H), 7.17-7.09 (comp m, 6H), 6.65 (d, J=7 Hz, 1H), 6.56 (d, J=7 Hz,1H), 5.64 (s, 1H), 4.73 (d, J=11 Hz, 1H), 4.40 (d, J=11 Hz, 1H), 3.50(d, J=6 Hz, 1H), 3.34 (d, J=18 Hz, 1H), 3.02 (d, J=16 Hz, 1H), 2.77-2.55(comp m, 3H), 2.42 (s, 3H), 2.36-2.27 (comp m, 2H), 1.68 (m, 1H).

EXAMPLE XI5,6,7,8,8a,9,14,14bβ-Octahydro-1,8aβ-dihydroxy-7-methyl-4,(R,.alpha.)-methano-7-(2-propenyl)-4bS*-benzofuro-[2,3-a]pyrido[4,3-b]carbazole-11-carboxylicacid, hydrochloride (Compound 11)

The title compound was prepared as described in Example V except thatnaloxone hydrochloride dihydrate was used in place of the oxymorphonehydrochloride. ¹ H NMR (CD₃ OD) δ8.18 (s, 1H), 7.81 (d, J=8 Hz, 1H),7.37 (d, J=8 Hz, 1H), 6.67 (comp m, 2H), 5.98 (m, 1H), 5.69 (s, 1H),5.73-5.64 (comp m, 2H), 3.86-2.64 (10H), 1.93 (m, 1H).

EXAMPLE XII5,6,7,8,14,14bβ-Hexahydro-13-iodo-7-methyl-4,8-(R,α)-methano-4bS*-benzofuro[2,3-a]pyrido[4,3-b]-carbazole-1,8aβ(9H)-diol,monohydrochloride (Compound 12)

The title compound was prepared as described in Example V except that2-iodophenyl hydrazine was used in place of the 4-hydrazinobenzoic acid.¹ H NMR (CD₃ OD) δ7.53 (d, J=8 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 6.77 (t,J=8 Hz, 1H), 6.68 (comp m, 2H), 5.76 (s, 1H), 3.81 (d, J=7 Hz, 1H), 3.51(d, J=16 Hz, 1H), 3.38-3.18 (4H), 2,967 (s, 3H), 2.72 (comp m, 2H), 1.95(m, 1H).

EXAMPLE XIII5,6,7,8,14,14bβ-Hexahydro-7-[[5-(hydroxymethyl)-2-furanyl]methyl]-4,8(R,α)-methano-4bS*-benzofuro[2,3-a]pyrido[4,3-b]carbazole-1,8aβ(9H)-diol,monohydrochloride (Compound 13)

The title compound was prepared by the method described in Example VIIexcept that 5-(hydroxymethyl)furfural was used in place of thephenylacetaldehyde. ¹ H NMR (CD₃ OD) δ7.48 (d, J=8 Hz, 1H), 7.41 (d, J=8Hz, 1H), 7.31 (t, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H), 6.72 (comp m, 3H),6.46 (d, J=3 Hz, 1H), 5.68 (s, 1H), 4.61 (s, 2H), 4.42 (m, 1H),3.70-2.60(9H), 2.00 (m, 1H).

EXAMPLE XIV7-(3-Furanylmethyl)-5,6,7,8,14,14bα-hexahydro-4,8(R,α)-methano-4bS*-benzofuro[2,3-a]pyrido-[4,3-b]carbazole-1,8aβ(9H)-diol,hydrochloride (Compound 14)

The title compound was prepared by the method described in Example VIIexcept that 3-furaldehyde was used in place of the phenylacetaldehyde. ¹H NMR (CD₃ OD) δ7.88 (s, 1H), 7.72 (s, 1H), 7.46 (d, J=8 Hz, 1H), 7.41(d, J=8 Hz, 1H), 7.32 (t, J=8 Hz, 1H), 7.21 (t, J=8 Hz, 1H), 6.73 (compm, 3H), 5.70 (s, 1H), 4.50 (d, J=15 Hz, 1H) , 4.28 (d, 15 Hz, 1H) ,3.60-2.60 (8H), 2.08 (m, 1H).

EXAMPLE XV5,6,7,8,14,14bβ-Hexahydro-(1H-imidazol-2-ylmethl)-4,8(R,α)-methano-4bS*-benzofuro[2,3-a]pyrido-[4,3-b]carbazole-1,8aβ(9H)-diol,hydrochloride (Compound 15)

The title compound was prepared by the method described in Example VIIexcept that 2-imidazolecarboxaldehyde was used in place of thephenylacetaldehyde. ¹ H NMR (CD₃ OD) δ7.65 (s, 2H), 7.47 (comp m, 2H),7.30 (t, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H), 6.68 (comp m, 3H), 5.65 (s,1H), 4.52 (comp m, 2H) , 3.55-2.60 (8H) , 1.90 (m, 1H) .

EXAMPLE XVI6,7,8,14bβ-Tetrahydro-7-(2-phenylmethyl)-4,8-(R,α)-methano-4bS*-5H-bisbenzofuro-[3,2-e:2',3'-g]isoquinoline-1,8aβ(9H)-diol(Compound 16)

6,7,8,14bβ-Tetrahydro-4,8(R,α)-methano-4bS*-5H-bisbenzofuro[3,2-e:2',3'-g]isoquinoline-1,8aβ(9H)-diol(125 mg, 0,346 mmol) was slurried in dimethylformamide (3 mL). Potassiumcarbonate (53 mg, 0.38 mmol) and benzyl bromide (65 mg, 0.38 mmol) wereadded and the resulting mixture was heated to 90°-100° C. for 3 hours.The mixture was cooled to room temperature and diluted with water (25mL) before extracting with chloroform (2×25 mL). The combined organicextracts were evaporated in vacuo to give a residue which was purifiedby silica gel chromatography, eluting with 10% methanol in methylenechloride. The product was recrystallized from isopropyl ether/hexane togive the title compound as a white solid. ¹ H NMR (CDCl₃) δ7.45 (d, J=8Hz, 1H), 7.39-7.24 (comp m, 7H), 7.16 (t, J=8 Hz, 1H), 6.67 (d, J=8 Hz,1H), 6.61 (d, J=8 Hz, 1H), 5.63 (s, 1H), 4.87 (br s, 1H), 4.69 (br s,1H), 3.71 (br s, 2H), 3.32 (d J=18 Hz, 1H), 3.12 (d, J=7 Hz, 1H),2.96-2.37 (comp m, 6H), 1.72 (d, J=10 Hz, 1H).

(6) Description of the Assays

The biological activities of the compounds of this invention weredetermined by the following test procedures.

(a) Writhing Assay

The Writhing Assay is one of the most widely-used experimentalprocedures for measuring the analgesic activity of different narcoticand nonnarcotic analgesic agents, and involves the continuous,chemically-induced pain of visceral origin to an animal, such as a mouseor rat. [Gyires et al., Arch. int. Pharmacodyn, 267, 131-140 (1984); C.Vander Wende et al., Fed. Proc., 15, 494 (1956); Koster et al., Fed.Proc., 18, 412 (1959); and Witken et al., J. Pharmacol. exp. Ther., 133,400-408 (1961).] Chemicals which may be used to induce this pain includephenylbenzoquinone (PBQ) and acetic acid. As a result of the chemicalirritation to the animal, a characteristic stretching and writhing ofthe animal (dorsiflexion of the animal's back, extension of itshindlimbs and the strong contraction of its abdominal musculature) willgenerally occur. The intensity of this pain reaction is determined bythe number of writhes exhibited by the animal during a given period oftime. Drugs which reduce the number of writhes of the animal appear torestore the normal nociceptive threshold of the animal.

Compounds of the present invention exhibit analgesic activity in mice,as shown by the results of the Writhing Assay presented in Table Ibelow.

Charles River male albino mice, weighing 20 to 30 grams were used inthis assay.

Thirty minutes after subcutaneous or intragastric administration to tenmice of either 10 mg or 30 mg per kilogram of body weight of a compoundof the present invention ("test compound"), 0.1 mg per 10 g of bodyweight of a 0.025% w/v solution of PBQ was injected intraperitoneallyinto each mouse. Ten mice which were given saline in place of a testcompound of the invention were used as a control group.

Five minutes later, each mouse was individually placed into a glassbeaker for observation, and the number of writhes occurring during thefollowing ten-minute period was counted.

A test compound was considered to have produced analgesia in a mouse if,in accordance with the conditions set forth above, and under the testcriteria employed for this assay, after the administration of 10 or 30mg per kilogram of body weight of a compound of the present invention tothe mouse, the number of writhes elicited by a mouse injected with PBQwas equal to, or less than, one-half the median number of writhesrecorded for the saline-treated control group of mice that day, asdescribed by Taber in "Predictive Value of Analgesic Assays in Mice andRats," Advances in Biochemical Psychopharmacology, 8, 191 (1974).

The results for the particular compounds of the present inventionanalyzed in this assay, and discussed in the examples identified belowwhich correspond thereto, are presented in Table I hereinbelow asfractions under the heading "PBQ Writhing Assay." The fractions indicatethe number of mice, out of ten, in which the test compound producedanalgesia in accordance with the conditions set forth above, and underthe test criteria employed for this assay.

The standard initial screening doses of a test compound employed in thisassay were 10 and/or 30 mpk per gram of body weight for both routes ofadministration. If the initial screening dose of the compound producedanalgesia in seven of ten mice, then the effect of additional doses ofthe compound on the writhing response was evaluated, and then the ED₅₀dose was generally calculated. (The slopes of the dose-response curvesfor the compounds analyzed were compared as described by Tallarida andMurray, Manual of Pharmacologic Calculations, Page 11 (Springer Verlag,New York, 1981)).

All ED₅₀ doses calculated are also presented below as whole numbers inTable I under the heading "PBQ WRITHING ASSAY." As Table I shows, themost potent compound of the present invention tested in the WrithingAssay was the compound shown and discussed in Example V.

                  TABLE 1                                                         ______________________________________                                        Data Generated from the Writhing Assay                                        PBQ WRITHING ASSAY                                                                           (ED.sub.50 {mpk})                                              EXAMPLE NUMBER   I.G.          S.C.                                           ______________________________________                                        I                inactive at the initial                                                                     2.4                                                             screening dose                                               II               4/10*         4/10*                                          V                3.4           1.3                                            ______________________________________                                         *Number of mice in 10 exhibiting inhibition of writhing                  

(b) Tail Flick Assay

The "Tail Flick Assay" uses thermal pain of transient duration, and is atest in which the pain threshold of the mice or rats being analyzed hasnot been altered. It is useful for evaluating the ability of a compoundor drug to increase the animal's pain threshold (i.e. prolong responselatencies), rather than to restore normal thresholds.

The heat-induced response to the Tail Flick Assay is a reflex reactionmediated at the level of the spinal cord.

Opiate compounds having clinical efficacy as analgesics generallyincrease tail flick latencies. Thus, morphine and codeine are generallydetermined to be active in this test. In contrast, aspirin and Zomax,which are Non--Steroidal Antiinflammatory Drugs (NSAIDs), show littleactivity in this test.

The Tail Flick Assay was performed generally in the manner described byG. Woolfe et al., "The Evaluation of the Analgesic Action of PethidineHydrochloride (Demerol)," J. Pharmacol. Exp. Ther., 80, 300, (1944), F.D'Amour et al., "A Method for Determining Loss of Pain Sensation," J.Pharmacol Exp. . Ther., 72, 74, 300-307 (1941), and E. Drower et al.,"The Antinociceptive Effects of Prostaglandin Antagonists in the Rat,"European Journal of Pharmacology, 133, 249-256 (1987).

Male Charles River albino mice, and male Charles River Sprague-Dawleyrats, weighing 20 to 30 g, and 200 to 250 g, respectively, were employedin this assay.

Tail flick response latencies (defined as the time that elapsed betweenthe onset of a high intensity beam of light and the reflex removal ofthe mouse or rat's tail) was measured before (baseline) and again atfixed intervals after subcutaneous or intracerebroventricularadministration of one of the compounds of the invention, or after theadministration of saline (controls). The cut-off latencies establishedto prevent tissue damage in the animals are 12 seconds or 14 seconds inthe mouse and rat, respectively, in the Tail Flick Assay. Thesignificance of any increase in tail flick response latency isdetermined using analyses of variance.

One way analyses of variance were used to determine the significance ofthe effect of the compounds of the invention on response latencies. Forthis assay, the ED₅₀ value was defined as the dose of a compound whichproduced one half the maximum possible increase in latency (i.e., to 7.5and 8.5 seconds in the mouse and rat, respectively). Calculations ofED₅₀ values were based upon a least squared linear regression equationcomputed for the data at a time of peak effect, as described by D'Amourand Woolfe, supra.

"Activity" or "Inactivity" was determined at a particular concentrationof the compound by a significant increase in tail flick latency abovenormal latencies.

The data resulting from the Tail Flick Assay are presented in Table IIbelow.

                  TABLE II                                                        ______________________________________                                        Data Generated from the Tail Flick Assay                                                                   Intracerebro-                                    Compound Tested                                                                             Subcutaneous   ventricular                                      Example Number                                                                              (S.C.)         (I.G.)                                           ______________________________________                                        IX            active at >30 mpk                                                                             10.5 nmoles                                     XV            inactive       ˜10 nmoles                                 ______________________________________                                    

The data presented in Table II show that, when administeredintracerebroventricularly, the compounds of examples IX and XV areactive at a dose of ca. 10 nmoles.

(3) Opiate Binding Assay

Compounds within the present invention were also evaluated in an opioidradioligand binding assay, which measures the affinity of opioids forspecific opioid receptors in rat forebrain, by their ability to displacethe binding of radiolabeled ligands specifically bound to μ and/or δopioid receptors isolated from rat brain. Compounds which are determinedto be active in this in vitro assay will generally have opioid-likeeffects in animals, including analgesia, unless they are notbioavailable.

A purified homogenate of receptor membranes was prepared from the brainsof the rats according to the method described by K. J. Chang et al.,"Multiple Opiate Receptors: Enkephalins and Morphine Bind to Receptorsof Different Specitivity," J. Biol Chem., 254, 2610-2618 (1979).

Male Charles River Sprague-Dawley albino rats weighing 150 to 300 g werestunned and decapitated. Their forebrains (minus the cerebellum andassociated hindbrain) were quickly removed and rinsed in ice-cold 50 mMTris buffer, pH 7.4, and homogenized in 20 volumes of buffer with aPolytron (Brinkman) at setting 6 for 30 seconds. The membranes werewashed by centrifugation for 20 minutes at 30,000×g, followed byresuspension to twice the original volume. The homogenate was incubatedat 25° for 1 hour, followed by centrifugation as above.

The resulting homogenate was then assayed for protein content accordingto the method described by Itzhaki et al., "A Micro-Biuret Method forEstimating Proteins," Anal Biochem., 9, 401-410 (1961) The final pelletwas resuspended to a protein concentration of 10 mg protein per mL(assuming 6% of wet weight is protein) and 4 mL aliquots were rapidlyfrozen in liquid N₂.

The binding of compounds within the invention to the rat brain opiatereceptor membrane preparation containing either δ or μ opioid receptorswas measured using a modification of the method of C. B. Pert et al.,"Properties of Opiate Receptor Binding in Rat Brain, "Proc Natl AcadSci., 70, 2243-2247 (1972).

The opiate binding assays were conducted in triplicate at 37° C. in 50mM TrisHCl buffer at pH 7.4 in a final volume of 1 mL, using varyingconcentrations of a compound of the invention. Each of three tubescontained 0.8 mL of homogenate containing approximately 1 mg/mL ofprotein. ³ [H]-DAMGO (2.0 nM) and ³ [H]-DSLET (1.0 nM) were used tolabel the μ and δ opiate rat brain receptors, respectively.

The "per cent displacement" of radiolabeled ligand (³ [H]-DAMGO for theμ receptors and ³ [H]-DSLET for the δ receptors) bound to the μ or δopioid receptors by a compound of the present invention was determinedat different concentrations of the compound (10 μM, 1 μM, 100 nM and/or1 nM). Because the radiolabeled ligand and the compound compete witheach other for the opiate receptor binding sites, the greater the percent of displacement of the bound radiolabeled ligand, the better thecompound is in terms of its ability to bind to the opiate receptors and,thus, the more potent the compound is. "Specific binding" of a compoundof the present invention to the μ or the δ opiate rat brain receptorswas defined as the difference between total binding and that in thepresence of 10 μM of levorphanol.

For those compounds which bound particularly well to the opiatereceptors, the mean IC₅₀ value (that concentration of a particularcompound which is required to have 50 per cent of the bound radiolabeledligand displaced from the opiate receptors) was calculated (nM). IC₅₀values were determined from log-logit plots of concentration vs. timeresponse curves. Comparison of IC₅₀ values in this assay system providesa measure of the receptor specificity of the tested compounds.

Finally, for those compound for which a mean IC₅₀ value was calculatedfor both the μ and δ opioid receptors, the ratio of the mean IC₅₀ valuesfor the μ and δ opioid receptors was determined. This ratio indicateshow specific a particular compound is for the δ opioid receptors. Thus,if the ratio of the mean IC₅₀ values is 1.0, the compound isapproximately equally specific for both the μ and the δ opioidreceptors. The greater the number is above 1.0, the more specific thecompound is for the δ opioid receptors.

The results obtained from this opiate binding assay are shown in TableIII below, and correspond to the compound shown and described in theparticular example identified below which corresponds thereto.

                  TABLE III                                                       ______________________________________                                        Data Obtained from the Opiate Binding Assay                                   Example    Per Cent    Mean IC.sub.50                                                                            Mean IC.sub.50                             Number     Displacement                                                                              Value       μ/δ Ratio                         ______________________________________                                        Example (δ)                                                                            14% at 100 nM                                                  Example (μ) 2           291       45                                       II      (δ)          6.5       45                                       Example (μ)             4670      91                                       III     (δ)          51.1      91                                       Example (μ)             >10000    >850                                     IV      (δ)          11.8      >850                                     Example (μ)             810       1.2                                      V       (δ)          660       1.2                                      Example (μ)             248       3.8                                      VI      (δ)          65        3.8                                      Example (μ) 35% at 1 μM                                                                            N C       --                                       VII     (δ)          34.5      --                                       Example (μ)             4000      25                                       VIII    (δ)          160       25                                       Example (μ)             430       430                                      IX      (δ)          1         430                                      Example (μ)             356       44                                       X       (δ)          8         44                                       Example (μ)             101       10.6                                     XII     (δ)          9.5       10.6                                     Example (μ)             inactive  --                                       XIII    (δ)          ˜100                                                                              --                                       Example (μ)             inactive  --                                       XIV     (δ)          31.8      --                                       Example (μ)             inactive  --                                       XV      (δ)          79.2      --                                       Example (μ)             inactive  --                                       XVI     (δ)          50% at 50 nM                                                                            --                                       ______________________________________                                         --= Not Applicable (Because the Mean IC.sub.50 Value was not Calculated)      N C = Not calculated                                                     

(7) Dosage and Mode of Administration

The compounds of the present invention, and the pharmaceuticalcompositions comprising one or more of these compounds in combinationwith a pharmaceutically-acceptable carrier, are useful in treating painin animals. A physician or veterinarian of ordinary skill in the art canreadily determine whether or not a particular patient is in pain.

The pharmaceutical compositions of the present invention, which willtypically comprise one or more of the compounds of Formula I as anactive ingredient in admixture with one or morepharmaceutically-acceptable carriers and, optionally, with one or moreother compounds, drugs or materials, are employed therapeutically and,thus, would generally be used under the guidance of a physician. Theappropriate dosage and form of administration of these compositions willbe suitably selected by methods which are consistent with conventionalpharmaceutical practices.

The pharmaceutical compositions of the present invention may bespecially formulated for oral administration in solid or liquid form,for parenteral injection, and/or for rectal or vaginal administration.They may be administered to humans and other animals for therapy by anysuitable route of administration, including orally, nasally, as by, forexample, a spray, rectally, intravaginally, parenterally,intracisternally and topically, as by powders, ointments or drops,including buccally and sublingually. While the preferred routes ofadministration are orally and parenterally, the most preferred mode ofadministration is orally.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the severity of the pain, theduration of the treatment, other drugs, compounds and/or materials usedin combination with the particular compound employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required to alleviate or ameliorate a particular patient'spain. For example, the physician or veterinarian could start doses ofthe compound of the invention employed in the pharmaceutical compositionat levels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound of the present inventionwill be that amount of the compound which is the lowest dose effectiveto produce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, dosage levels in therange of from about 0.001 mg to about 10 g, more preferably from about 1mg to about 1000 mg, of active compound (a compound of Formula I) perkilogram of body weight per day are administered to a mammalian patient.However, the total daily usage of the compounds of Formula I, or thepharmaceutical compositions comprising such compounds, will bedetermined by an attending physician or veterinarian within the scope ofsound medical judgement.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical formulation (composition).

The pharmaceutical compositions of the present invention comprise acompound of the present invention together with one or morepharmaceutically-acceptable carriers thereof and, optionally, with othertherapeutic agents. Each carrier must be "acceptable" in the sense ofbeing compatible with the other ingredients of the formulation and notinjurious to the patient.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfite, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient (compoundof Formula I) which can be combined with a carrier material to produce asingle dosage form will vary depending upon the host being treated, theparticular mode of administration and all of the other factors describedabove. The amount of active ingredient which can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound which is the lowest dose effective to produce atherapeutic effect. Generally, out of one hundred per cent, this amountwill range from about 1 per cent to about ninety-nine percent of activeingredient, preferably from about 5 per cent to about 70 per cent, mostpreferably from about 10 per cent to about 30 per cent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient (compound of Formula I) is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds; (7) wetting agents, such as, for example, cetylalcohol and glycerol monostearate; (8) absorbents, such as kaolin andbentonite clay; (9) lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and (10) coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile, injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically-acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient (compound of Formula I), the liquid dosage forms may containinert diluents commonly used in the art, such as, for example, water orother solvents, solubilizing agents and emulsifiers, such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, wheat germ, olive, andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof,

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the invention to the body. Such dosage formscan be made by dissolving, dispersing or otherwise incorporating acompound of the present invention in a proper medium, such as anelastomeric matrix material. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate of such fluxcan be controlled by either providing a rate-controlling membrane ordispersing the compound in a polymer matrix or gel.

Opthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol, sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable dosage forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of drug to polymer, and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissue.

The injectable materials can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or in other sterile injectable media justprior to use.

The formulations may be presented in unit-dose or multi-dose sealedcontainers, for example, ampoules and vials, and may be stored in alyophilized condition requiring only the addition of the sterile liquidcarrier, for example water for injections, immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the type described above.

The pharmaceutical compositions of the present invention may also beused in the form of veterinary formulations, including those adapted forthe following: (1) oral administration, for example, drenches (aqueousor non-aqueous solutions or suspensions), tablets, boluses, powders,granules or pellets for admixture with feed stuffs, pastes forapplication to the tongue; (2) parenteral administration, for example,by subcutaneous, intramuscular or intravenous injection as, for example,a sterile solution or suspension or, when appropriate, by intramammaryinjection where a suspension or solution is introduced into the udder ofthe animal via its teat; (3) topical application, for example, as acream, ointment or spray applied to the skin; or (4) intravaginally, forexample, as a pessary, cream or foam.

What is claimed is:
 1. A compound of the formula: ##STR35## or apharmaceutically-acceptable salt thereof, wherein: R¹ is --CN;R² is[--OR⁴ wherein R⁴ is ##STR36## alkyl; R³ is ##STR37## alkyl or alkoxy; Xis O; and Y is hydrogen.
 2. A compound of the formula: ##STR38## or apharmaceutically-acceptable salt thereof, wherein: R¹ is hydrogen;R² is--OH; R³ is hydrogen; X is O; and Y is hydrogen.
 3. A compound of theformula: ##STR39## or a pharmaceutically-acceptable salt thereof,wherein: R¹ is C₃ -C₆ alkenyl;R² is --OH; R³ is hydrogen; X is O; and Yis hydrogen.
 4. A compound of the formula: ##STR40## or apharmaceutically-acceptable salt thereof, wherein: R¹ is ##STR41## R is--H or --C₁ -C₅ alkyl; n is an integer of from 1 to 5;R² is --OH; R³ ishydrogen; X is O; and Y is hydrogen.
 5. A compound having the structure:##STR42##
 6. A compound having the structure: ##STR43##
 7. A compoundhaving the structure: ##STR44##
 8. A compound of the formula: ##STR45##or a pharmaceutically-acceptable salt thereof, wherein R¹ represents--A--B, wherein A is alkylene having one or two carbon atoms and B isphenyl.
 9. A compound of the formula: ##STR46## or apharmaceutically-acceptable salt thereof, wherein n is an integer offrom 1 to
 5. 10. A compound of the formula: ##STR47## or apharmaceutically-acceptable salt thereof, wherein: R¹ is C₁ -C₆ alkyl;andR⁴ is C₁ -C₅ alkyl.
 11. A compound of the formula: ##STR48## or apharmaceutically-acceptable salt thereof, wherein R¹ is C₁ -C₆ alkyl.12. A compound of the formula: ##STR49## or apharmaceutically-acceptable salt thereof, wherein R¹ is --A--B, whereinA is alkylene having one or two carbon atoms and B is phenyl, ##STR50##13. A compound of the formula: ##STR51## or apharmaceutically-acceptable salt thereof, wherein R¹ is --C₁ -C₆ alkyland Y is --CO--OH or --CO--O--C₁ -C₅ alkyl.